Periodic Reporting for period 3 - RISCC (RISK-BASED SCREENING FOR CERVICAL CANCER)
Período documentado: 2023-01-01 hasta 2024-06-30
Cervical cancer (CC) is preventable through vaccination or detection in a precancerous state, but still the 4th most common cancer in women worldwide. In Europe alone in 2018, 61,000 new cases and 25,000 deaths were reported. 70% of the EU citizens have access to organized CC screening which decreased incidence and mortality rate up to 70%. Nevertheless, CC is still common and even rising in several European countries.
Most screening programs report a high proportion of unnecessary colposcopy referrals. The lack of efficiency is also reflected in the number of screening invitations which varies from 7 to >40 between European countries, but is not clearly associated with the country-specific CC incidence. This suggests considerable overconsumption in regions. To eliminate CC as a public health problem, the effectiveness and efficiency of screening programs and resources should be directed to those most at risk. Current one-size-fits-all protocols can be drastically improved. “Risk-based Screening for Cervical Cancer” (RISCC) aims to develop and evaluate the first risk-based screening program for CC, provide open-source implementation tools and contribute to the elimination of CC in Europe.
Most screening programs report a high proportion of unnecessary colposcopy referrals. The lack of efficiency is also reflected in the number of screening invitations which varies from 7 to >40 between European countries, but is not clearly associated with the country-specific CC incidence. This suggests considerable overconsumption in regions. To eliminate CC as a public health problem, the effectiveness and efficiency of screening programs and resources should be directed to those most at risk. Current one-size-fits-all protocols can be drastically improved. “Risk-based Screening for Cervical Cancer” (RISCC) aims to develop and evaluate the first risk-based screening program for CC, provide open-source implementation tools and contribute to the elimination of CC in Europe.
WP2 aims to develop CC risk profiles for screen-eligible women based on their screening history, whether obtained by self-sampling or a physician-collected cervical sample. The WP2 database was updated and the following analyses performed:
1. the analyses of the Slovenian cohort over 9-year follow-up was completed (submitted for peer review).
2. the analyses of the Dutch IMPROVE self-sampling trial (6-year follow-up) was completed and will be presented (IPVC, 2024).
3. A screening history analysis of the Swedish registry data was completed (submitted)
Next to the epidemiological analyses, the statistical prevalence-incidence-cure model developed within RISCC was applied to the database to get accurate parameter estimates for the mathematical model (WP5), leading to increased understanding of the CIN3 risk differences between countries.
IMPROVE trial data samples were used for DNA methylation analysis, focusing on ASCL1/LHX8 (instead of HPV) as a potential primary screening test. All samples (HPV+ at baseline) were tested for methylation, showing that it may be considered as primary test in young women, but not >30 years (low specificity).
WP3 aims to develop CC risk profiles in 1992-1995 birth cohorts vaccinated against HPV in settings with varying vaccination and screening coverage exploiting a randomized study setting for vaccinated women (Screening study (SS) 1) and herd effect protected unvaccinated women (born 1996/7- SS 2). In addition, an observational study is done in vaccinated women (born 1992-1998). The 3 consecutive SS1 visits (ages 22, 25 and 28) were completed (overall 93% compliance), and SS2 end-point visits (age 28) are ongoing with ~ 77% compliance. Identical accuracy of (in)frequent screening in the identification HSILs was documented in SS1, which is pivotal for the development of pertinent CC risk profiles and required screening algorithm by vaccination status/policy.
Meta-analytical work was performed in WP4 on the following topics:
- HPV tests that fulfil clinical validation criteria for use in CC screening
- New criteria for 2nd generation standard comparator tests to be used in future validation studies on new HPV assays
- IPD on adverse obstetrical risk associated with treatment of cervical precancer
- Continuous update of differences in response rate (under-screened women received a self-sampling device vs. an invitation to contact a clinician to take a cervical specimen)
- Extension on the relative accuracy of HPV testing on self- vs. clinician-taken samples
- Performance of mRNA HPV assays in CC screening
- Study plan to assess performance of extended HPV genotyping in triage of HPV+ women.
In WP5 a microsimulation model was developed of multiple oncogenic HPV infection progression to CC designed to compare the (cost-)effectiveness of different CC screening algorithms adapted to specific risk profiles. CC screening across Europe was assessed and a contextualized list of risk-based screening algorithms, reflecting the current status of risk-based screening across Europe was designed to be applied for setup an EU-wide framework. A framework and tools were developed to be able to model any generic EU country with sufficient data to inform the natural-history model. We will assess the optimal balance between effectiveness and screening-related harms and quantify the resource associated with risk-based screening algorithms across European countries.
In WP6 we pioneered the risk-based screening concept developing the required eHealth/mHealth platforms, and implementing them in a national screening program in Sweden and launch of a pilot risk-based screening project in Hungary.
Previously, WP6 reported on the ethical aspects and permissions for risk-stratified screening, on use of the Swedish screening registry to identify the CC risk, and on the standardized data model and design of an Open Source software with eConsent module to invite high-risk participants to order a self-sampling kit. The outcome of these studies gave us ample power to evaluate the key outcome variables described in the ToR (participation, actual resource use and safety/yield).
The software platform (Open Source through GitHub) installed at KI was customized for reuse by design of a multilanguage version and new languages can easily be added and every country can have its own web-service environment. The information is stratified regarding users, resources, and study participants.
WP7 includes all dissemination and communication activities related to RISCC, including a website, a twitter account, a project leaflet, biannual newsletters, a commissioned project summary paper, an HPV world issue on RISCC and other European results on screening and vaccination and participation in the Horizon results booster.
A free online course on CC screening was developed targeting European healthcare providers and management willing to implement HPV-based screening. ~4500 students signed in for several Spanish editions (https://www.e-oncologia.org/cursos/cuello-uterino-prevencion-y-cribado/). An updated and more interactive version in English will be released at the end of the project.
ESGO/ENGAGe has partners within 70+ countries Europe-wide reaching most European women. For RISCC certain countries (RISCC Ambassadors) have been determined to communicate on the importance of risk-based screening and the benefits it can bring to the women, the clinicians and financial budgets on national health systems.
WP8 concerns all ethical issues in the project, all deliverables were submitted.
1. the analyses of the Slovenian cohort over 9-year follow-up was completed (submitted for peer review).
2. the analyses of the Dutch IMPROVE self-sampling trial (6-year follow-up) was completed and will be presented (IPVC, 2024).
3. A screening history analysis of the Swedish registry data was completed (submitted)
Next to the epidemiological analyses, the statistical prevalence-incidence-cure model developed within RISCC was applied to the database to get accurate parameter estimates for the mathematical model (WP5), leading to increased understanding of the CIN3 risk differences between countries.
IMPROVE trial data samples were used for DNA methylation analysis, focusing on ASCL1/LHX8 (instead of HPV) as a potential primary screening test. All samples (HPV+ at baseline) were tested for methylation, showing that it may be considered as primary test in young women, but not >30 years (low specificity).
WP3 aims to develop CC risk profiles in 1992-1995 birth cohorts vaccinated against HPV in settings with varying vaccination and screening coverage exploiting a randomized study setting for vaccinated women (Screening study (SS) 1) and herd effect protected unvaccinated women (born 1996/7- SS 2). In addition, an observational study is done in vaccinated women (born 1992-1998). The 3 consecutive SS1 visits (ages 22, 25 and 28) were completed (overall 93% compliance), and SS2 end-point visits (age 28) are ongoing with ~ 77% compliance. Identical accuracy of (in)frequent screening in the identification HSILs was documented in SS1, which is pivotal for the development of pertinent CC risk profiles and required screening algorithm by vaccination status/policy.
Meta-analytical work was performed in WP4 on the following topics:
- HPV tests that fulfil clinical validation criteria for use in CC screening
- New criteria for 2nd generation standard comparator tests to be used in future validation studies on new HPV assays
- IPD on adverse obstetrical risk associated with treatment of cervical precancer
- Continuous update of differences in response rate (under-screened women received a self-sampling device vs. an invitation to contact a clinician to take a cervical specimen)
- Extension on the relative accuracy of HPV testing on self- vs. clinician-taken samples
- Performance of mRNA HPV assays in CC screening
- Study plan to assess performance of extended HPV genotyping in triage of HPV+ women.
In WP5 a microsimulation model was developed of multiple oncogenic HPV infection progression to CC designed to compare the (cost-)effectiveness of different CC screening algorithms adapted to specific risk profiles. CC screening across Europe was assessed and a contextualized list of risk-based screening algorithms, reflecting the current status of risk-based screening across Europe was designed to be applied for setup an EU-wide framework. A framework and tools were developed to be able to model any generic EU country with sufficient data to inform the natural-history model. We will assess the optimal balance between effectiveness and screening-related harms and quantify the resource associated with risk-based screening algorithms across European countries.
In WP6 we pioneered the risk-based screening concept developing the required eHealth/mHealth platforms, and implementing them in a national screening program in Sweden and launch of a pilot risk-based screening project in Hungary.
Previously, WP6 reported on the ethical aspects and permissions for risk-stratified screening, on use of the Swedish screening registry to identify the CC risk, and on the standardized data model and design of an Open Source software with eConsent module to invite high-risk participants to order a self-sampling kit. The outcome of these studies gave us ample power to evaluate the key outcome variables described in the ToR (participation, actual resource use and safety/yield).
The software platform (Open Source through GitHub) installed at KI was customized for reuse by design of a multilanguage version and new languages can easily be added and every country can have its own web-service environment. The information is stratified regarding users, resources, and study participants.
WP7 includes all dissemination and communication activities related to RISCC, including a website, a twitter account, a project leaflet, biannual newsletters, a commissioned project summary paper, an HPV world issue on RISCC and other European results on screening and vaccination and participation in the Horizon results booster.
A free online course on CC screening was developed targeting European healthcare providers and management willing to implement HPV-based screening. ~4500 students signed in for several Spanish editions (https://www.e-oncologia.org/cursos/cuello-uterino-prevencion-y-cribado/). An updated and more interactive version in English will be released at the end of the project.
ESGO/ENGAGe has partners within 70+ countries Europe-wide reaching most European women. For RISCC certain countries (RISCC Ambassadors) have been determined to communicate on the importance of risk-based screening and the benefits it can bring to the women, the clinicians and financial budgets on national health systems.
WP8 concerns all ethical issues in the project, all deliverables were submitted.
RISCC expects to establish effective, affordable and acceptable risk-based screening strategies. These will improve health outcomes and equity across Europe and show the potential of risk-based screening for CC and other diseases. Several steps have been made to develop risk profiles based on screening history, vaccination coverage and individual risk factors. A pilot using (m-)health/e-health solutions to facilitate risk-based screening was done in Sweden and is ongoing in Hungary. Besides dissemination and communication activities for researchers and other stakeholders, strong efforts were made to engage women and ensure proper communication to laypeople, through local ambassadors.